1 Jean-Charles Preiser Séminaire des services d’urgences IRIS Bruxelles, 10 mars 2009 Diabète et urgences Contrôle de la glycémie et amélioration du pronostic des affections graves muscles glucose glucose cerveau acides gras acides gras érythrocytes Lymphocytes G.Blancs intestin glutamine foie foie Tissus Tissus agress agressés lactate lactate Adaptations métaboliques à l’agression Insulino-résistance alanine alanine adipocytes glycérol Insulino-résistance Insulino Insulino ind indépendance pendance SEMINAIRES IRIS
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1
Jean-Charles Preiser
Séminaire des services d’urgences IRISBruxelles, 10 mars 2009
� 3,896 patients with diabetes undergoingcardiac surgery procedures
� Insulin IV vs s/c
� RRR of death 57%� RRR of deep sternal wound infection 66%
INTENSIVE INSULIN PROTOCOL IN
TRAUMA PATIENTSReed J Am Coll Surg 2007;204:1048
� Before / after implementation of an IIT protocolSE
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INTENSIVE INSULIN PROTOCOL IN
TRAUMA PATIENTSReed J Am Coll Surg 2007;204:1048
� Before / after implementation of an IIT protocol
� Clinical outcomes :� Reduction in mortality
INTENSIVE INSULIN PROTOCOL IN
TRAUMA PATIENTSReed J Am Coll Surg 2007;204:1048
� Before / after implementation of an IIT protocol
� Clinical outcomes :� Reduction in mortality� Reduction in the frequency of intraabdominal
abscesses (2.7 % to 0.7 %, p<.01)� Reduction in ventilator days (3.1 + 0.3 to 2.4 +
0.2, p < .05)
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� All patients admitted to a surgical ICU (n = 1548)� Continuous intravenous insulin to control blood glucose� Randomized to 2 different blood glucose targets� Intensive treatment � 4.4 – 6.1 mmol/L
versus� Conventional treatment � 10.0 – 11.1 mmol/L� 200 – 300 g iv glucose on first day, EN or TPN thereafter
Greet Van den Berghe, M.D., Ph.D., P. Wouters, M.Sc., F. Weekers, M.D., Ch. Verwaest, M.D.,
Intensive Insulin Therapy in Critically Ill Patients
NNT = NNT = NumberNumber neededneeded to to treattreat
SECONDARY OUTCOME VARIABLES
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In-hospital survival in the intention-to-treat analysis and in the subgroup of patients with ICU stay > 3 days
-7% (p=0.31)
-18%(0.05)
No effect on survival by intention-to-treat analysis,Beneficial effect in patients with ICU stay > 3 days
VN Engl J Med 2006; 345: 449
DearDearDearDear Greet,Greet,Greet,Greet,
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on the on the on the on the toxictoxictoxictoxic effectseffectseffectseffects of of of of severesevereseveresevere hyperglycemiahyperglycemiahyperglycemiahyperglycemia
on the on the on the on the benefitbenefitbenefitbenefit of Intensive of Intensive of Intensive of Intensive InsulinInsulinInsulinInsulin therapytherapytherapytherapy in in in in LeuvenLeuvenLeuvenLeuven
I I I I feelfeelfeelfeel concernedconcernedconcernedconcerned by by by by
the case mixthe case mixthe case mixthe case mix
the the the the amountamountamountamount of IV glucoseof IV glucoseof IV glucoseof IV glucose
the proportion of patients the proportion of patients the proportion of patients the proportion of patients receivingreceivingreceivingreceiving steroidssteroidssteroidssteroids
the the the the delaydelaydelaydelay beforebeforebeforebefore improvementimprovementimprovementimprovement
the the the the risksrisksrisksrisks of of of of hypoglycemiahypoglycemiahypoglycemiahypoglycemia
the the the the workloadworkloadworkloadworkload
the issue of the issue of the issue of the issue of bloodbloodbloodblood glucose glucose glucose glucose variabilityvariabilityvariabilityvariability
the absence of the absence of the absence of the absence of benefitsbenefitsbenefitsbenefits in in in in somesomesomesome categoriescategoriescategoriescategories of patients (of patients (of patients (of patients (diabeticsdiabeticsdiabeticsdiabetics LOS <3d)LOS <3d)LOS <3d)LOS <3d)
Greet Van den BergheUZ Leuven
Greet Van den BergheUZ Leuven
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CALORIC INTAKE
101364673840SomeEN
979677758785Predom
PN
143 +60
141 +62
179 +64
179 +65
161 +64
160 +66
IV glucose
10 + 510 + 519 + 720 + 615 + 815 + 8Calories
IITCITIITCITIITCIT
<3d<3d>3d> 3dITTITT
Van den Berghe et al Van den Berghe et al DiabetesDiabetes 2006;55:31512006;55:3151
� Prospective, randomised, controlled, investigator-blinded and multicentric study
� Aimed at comparing the effects of two regimens of insulin therapy, respectively titrated to achieve a blood sugar level � between 4.4 and 6.1 mmol/l (80 - 110 mg/dl) : GROUP IIT� and between 7.8 and 10.0 mmol/l (140 - 180 mg/dl) :
GROUP LIT
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� Inclusion criteria� 18 years or older
� admitted in an ICU
� Exclusion criterion� Absence of signed informed consent
GLUCONTROLGLUCONTROLGLUCONTROLGLUCONTROL
GLUCONTROLGLUCONTROLGLUCONTROLGLUCONTROL
� 7 countries� Austria, Belgium, France, Israel, The
Netherlands, Slovenia and Spain.
� 21 units in 19 centres
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� 1108 recruited patients� 1101 randomized patients� Length of observation:
«« The The availableavailable mortalitymortalitydata data representsrepresents onlyonly 40%40%of the optimal informationof the optimal informationsize size requiredrequired to to reliablyreliablydetectdetect a plausible a plausible treatmenttreatmenteffecteffect. Possible. Possiblemethodologicalmethodological and and reportingreportingbiasesbiases weakenweaken inferencesinferences. . »»
PERIOPERATIVE INSULIN INFUSIONGandhi Mayo Clin Proc 2008
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Benefits and Risks of Tight Glucose Control
in Critically Ill AdultsWiener Wiener Larson JAMA 2008;300:933
� 29 trials – 8432 ICU patients � Hospital mortality did not differ between TGC and usual care
(21.6 vs 23.3%, RR 0.93 (0.85-1.03))
� No significant difference in mortality after stratification� By glucose goal (< 110 vs < 150 mg/dl)� By type of units (medical surgical or mixed)
� No significant decrease in need for new dialysis
� Decreased risk of septicemia (10.9 vs 13.4 % (RR 0.76 (0.56-0.97), significant only in the moderately TGC (target < 150 mg/dl)
� Increased risk of hypoglycemia (13.7 vs 2.5 (RR 5.13 (4.09-6.43))
CLINICAL EXPERIENCE WITH TIGHT
GLUCOSE CONTROL BY INTENSIVE
INSULIN THERAPYPreiser Devos Crit Care Med 2007;v35
� How does IIT work?� Optimal target for blood glucose� Is the absolute level or the variability of blood
glucose the most detrimental factor?� Is hypoglycemia life-threatening?
� Associated workload
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CLINICAL EXPERIENCE WITH TIGHT
GLUCOSE CONTROL BY INTENSIVE
INSULIN THERAPYPreiser Devos Crit Care Med 2007;v35
� How does IIT work?� Optimal target for blood glucose� Is the absolute level or the variability of blood
glucose the most detrimental factor?� Is hypoglycemia life-threatening?
� Non-neurologic� Delayed diagnosis of adrenal / liver failure (falsely
attributed to IIT)� Others ?
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Hypoglycemia and the brain
� Glucose is the obligatory metabolic fuel for the injured brain
� No cerebral stores of glucose� Glucose diffusion from plasma to
neurons and astrocytes (concentration-dependent)
� In case of severe hypoglycemia, fall of ATP and cortical activity (EEG)
� Potential roles of lactate / glycogenreleased from astrocytes as rescuesubstrates ?
Impact of TGC on cerebral glucose metabolismOddo et al Crit Care Med 2008;36:3233
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Impact of TGC on cerebral glucose metabolismOddo et al Crit Care Med 2008;36:3233
Predictors of brain energy crisis(multivariate logistic regressionadjusted for ICP and CPP) :Serum glucose and dose of insulin
Impact of TGC on cerebral glucose metabolismOddo et al Crit Care Med 2008;36:3233
Predictors of hospital mortality(logistic regression)Brain energy crisis 7.4 (1.4-39.5)*Glasgow Coma scale 1.1 (.96-1.3)CPP 1.01 (.97-1.04)ICP 1 (0.99-1.01)
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IS TGC SAFE?
� Risk of hypoglycemia increased 4- to 6- foldwhen applying tight glucose control (BG target 80-110 mg/dl)
� Incidence of hypoglycemia increased in mostseverely ill patients
� Causal relationship between hypoglycemiaand in mortality – neurological damage not completely excluded
Meanwhile :
Moving beyond tight glucose control to safe
effective glucose controlJames S Krinsley and Jean-Charles Preiser
Critical Care 2008, 12:3: 149
Instead of TGC, we propose a stepwise approach defining anew standard – Safe, Effective Glycemic Control (SEGC).SEGC involves, first, adoption of a safe glycemictarget appropriate to the skills, experience and available toolsof the ICU that does not result in a significant increase in therate of hypoglycemia. A glycemic target of 80 to 150 mg/dl isnot unreasonable for an ICU to choose initially; implementation can subsequently lead to downward revisionof the glycemic goal.
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CLINICAL EXPERIENCE WITH TIGHT
GLUCOSE CONTROL BY INTENSIVE
INSULIN THERAPYPreiser Devos Crit Care Med 2007;v35
� How does IIT work?� Optimal target for blood glucose� Is the absolute level or the variability of blood
glucose the most detrimental factor?� Is hypoglycemia life-threatening?
� Associated workload
0 10 20 30 40 50 60 70
Other
No perceived obstacles
Concern about the accuracy of POC glucose meters toguide glycemic control care
Lack of financial resources
Reluctance to have patients endure the pain of frequentfingersticks
Lack of familiarity with hospital inpatient glycemic controlguidelines
Not convinced of the benefits of glycemic control
Lack of nursing endorsement
Lack of local expertise in inpatient hyperglycemia/diabetesmanagement
Lack of standardized institutional policies related toglucose management
Lack of administrative resources
Lack of clinical resources
Lack of physician endorsement
Concern about causing hypoglycemia
Percentage of Respondents
Cook BC et al SCCM congress (poster #282)
Perceived obstacles to the implementation of TGC
US survey
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0
2
4
6
8
10
12
14
16
18
Time to reachtarget (h)
Maintenancein target(h/day)
Incidencesevere hypo
(%)
InterventionControl
2 2 cohortscohorts of 50 patientsof 50 patients
Control : Control : physicianphysician’’ss discretiondiscretion